Myocardial fibrosis is a severe global health problem due to its prevalence in all forms of cardiac diseases and direct role in causing heart failure. The discovery of efficient anti-fibrotic compounds has been hampered due to the lack of physiologically relevant models that can faithfully replicate disease-related phenotypes. Herein, we propose the Biowire II platform as a powerful tool for cardiac disease modeling and pre-clinical compound screening. The disease model is constructed to recapitulate contractile, biomechanical, and electrophysiological complexities of fibrotic myocardium. Additionally, we constructed a heteropolar integrated model with fibrotic and healthy cardiac tissues coupled together. The integrated model captures the regional heterogeneity of scar lesion, border zone and adjacent healthy myocardium. Through precision phosphoproteomics analysis, the Biowire disease model provides a comprehensive profile of molecular pathways and targets involved in fibrosis remodeling. To set up an analytical system for the investigation of therapeutic targets and time-dependent biological actions in disease progression, we developed another modified model to recapitulate non-genetic cardiomyopathy. The long-term tissue cultivation and real-time functional readouts enable monitoring of both acute and chronic cardiac responses to Angiotensin II (Ang II), a key mediator in cardiac physiology. Along with mapping of cytokine secretion and proteomic profiles, this model presents an opportunity to quantitatively measure the dynamic pathological changes that could not be otherwise identified in conventional animal and 2D models. A further optimized screening strategy is used to evaluate compounds that target Ang II-induced cardiac remodeling. Through assessing the effects of different compounds, the drug screening data implicated multifaceted cardioprotective effects of relaxin in restoring contractile function and reducing fibrotic remodeling. Overall, this thesis provides an engineered platform where cardiac disease remodeling can be explicitly studied over the pathological process, thereby enabling the investigation of new disease mechanisms and the discovery of potential drug candidates.